PMID- 31775160 OWN - NLM STAT- MEDLINE DCOM- 20201228 LR - 20210110 IS - 1740-634X (Electronic) IS - 0893-133X (Print) IS - 0893-133X (Linking) VI - 45 IP - 4 DP - 2020 Mar TI - Exosomal secretion of a psychosis-altered miRNA that regulates glutamate receptor expression is affected by antipsychotics. PG - 656-665 LID - 10.1038/s41386-019-0579-1 [doi] AB - The ability of small secretory microvesicles known as exosomes to influence neuronal and glial function via their microRNA (miRNA) cargo has positioned them as a novel and effective method of cell-to-cell communication. However, little is known about the role of exosome-secreted miRNAs in the regulation of glutamate receptor gene expression and their relevance for schizophrenia (SCZ) and bipolar disorder (BD). Using mature miRNA profiling and quantitative real-time PCR (qRT-PCR) in the orbitofrontal cortex (OFC) of SCZ (N = 29; 20 male and 9 female), BD (N = 26; 12 male and 14 female), and unaffected control (N = 25; 21 male and 4 female) subjects, we uncovered that miR-223, an exosome-secreted miRNA that targets glutamate receptors, was increased at the mature miRNA level in the OFC of SCZ and BD patients with positive history of psychosis at the time of death and was inversely associated with deficits in the expression of its targets glutamate ionotropic receptor NMDA-type subunit 2B (GRIN2B) and glutamate ionotropic receptor AMPA-type subunit 2 (GRIA2). Furthermore, changes in miR-223 levels in the OFC were positively and negatively correlated with inflammatory and GABAergic gene expression, respectively. Moreover, miR-223 was found to be enriched in astrocytes and secreted via exosomes, and antipsychotics were shown to control its cellular and exosomal localization in a cell-specific manner. Furthermore, addition of astrocytic exosomes in neuronal cultures resulted in a significant increase in miR-223 expression and a notable reduction in Grin2b and Gria2 mRNA levels, which was strongly inversely associated with miR-223 expression. Lastly, inhibition of astrocytic miR-223 abrogated the exosomal-mediated reduction in neuronal Grin2b expression. Taken together, our results demonstrate that the exosomal secretion of a psychosis-altered and glial-enriched miRNA that controls neuronal gene expression is regulated by antipsychotics. FAU - Amoah, Stephen K AU - Amoah SK AUID- ORCID: 0000-0001-5486-6027 AD - Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA. AD - Autophagy inflammation and metabolism (AIM) center, Albuquerque, NM, USA. FAU - Rodriguez, Brian A AU - Rodriguez BA AD - Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA. FAU - Logothetis, Constantine N AU - Logothetis CN AD - Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA. FAU - Chander, Praveen AU - Chander P AD - Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA. FAU - Sellgren, Carl M AU - Sellgren CM AD - Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. FAU - Weick, Jason P AU - Weick JP AD - Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA. FAU - Sheridan, Steven D AU - Sheridan SD AD - Center for Genomic Medicine, Chemical Neurobiology Laboratory, Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. AD - Center for Experimental Drugs and Diagnostics, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. AD - Department of Psychiatry, Harvard Medical School, Boston, MA, USA. FAU - Jantzie, Lauren L AU - Jantzie LL AD - Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA. FAU - Webster, Maree J AU - Webster MJ AD - Laboratory of Brain Research, Stanley Medical Research Institute, Chevy Chase, MD, USA. FAU - Mellios, Nikolaos AU - Mellios N AUID- ORCID: 0000-0002-0310-1144 AD - Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA. nmellios@salud.unm.edu. AD - Autophagy inflammation and metabolism (AIM) center, Albuquerque, NM, USA. nmellios@salud.unm.edu. LA - eng GR - P20GM121176/U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/International PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20191127 PL - England TA - Neuropsychopharmacology JT - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JID - 8904907 RN - 0 (Antipsychotic Agents) RN - 0 (MIRN223 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (NR2B NMDA receptor) RN - 0 (Receptors, N-Methyl-D-Aspartate) SB - IM MH - Animals MH - Antipsychotic Agents/*pharmacology/therapeutic use MH - Cells, Cultured MH - Exosomes/*drug effects/genetics/*metabolism MH - Female MH - Gene Expression MH - Humans MH - Male MH - Mice MH - Mice, Inbred C57BL MH - MicroRNAs/antagonists & inhibitors/*biosynthesis/genetics MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/*biosynthesis/genetics MH - Schizophrenia/drug therapy/genetics/*metabolism PMC - PMC7021900 EDAT- 2019/11/28 06:00 MHDA- 2020/12/29 06:00 PMCR- 2019/11/27 CRDT- 2019/11/28 06:00 PHST- 2019/06/29 00:00 [received] PHST- 2019/11/19 00:00 [accepted] PHST- 2019/10/24 00:00 [revised] PHST- 2019/11/28 06:00 [pubmed] PHST- 2020/12/29 06:00 [medline] PHST- 2019/11/28 06:00 [entrez] PHST- 2019/11/27 00:00 [pmc-release] AID - 10.1038/s41386-019-0579-1 [pii] AID - 579 [pii] AID - 10.1038/s41386-019-0579-1 [doi] PST - ppublish SO - Neuropsychopharmacology. 2020 Mar;45(4):656-665. doi: 10.1038/s41386-019-0579-1. Epub 2019 Nov 27.